T h e n e w e ng l a n d j o u r na l o f m e dic i n e
H e a l t h L aw, E t h i c s , a n d H u m a n R i g h t s
Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report
Michelle M. Mello, J.D., Ph.D., Steven N. Goodman, M.D., M.H.S., Ph.D.,
The tumult arising from revelations of serious ment began, some argued that the evidence of the
safety risks associated with widely prescribed inferior safety of rosiglitazone was strong enough
drugs, including rosiglitazone (Avandia, Glaxo­ to make the trial ethically unjustifiable. Two FDA
SmithKline), rofecoxib (Vioxx, Merck), and cele­ epidemiologists wrote in a 2008 memorandum
coxib (Celebrex, Pfizer), has led to widespread that a head­to­head trial “would be unethical and
recognition that improvement is needed in our exploitative” and that even a robust informed­
national system of ensuring drug safety. Notwith­ consent process could not overcome the prob­
standing federal legislation in 2007 that strength­ lem.9 This was not the consensus FDA view,
ened the authority of the Food and Drug Admin­ which was that the uncertainty regarding the
istration (FDA) in the postmarketing period,1 cardiovascular risks associated with rosiglitazone,
critical weaknesses in the national system persist. as well as those associated with pioglitazone,
Central to these weaknesses are dilemmas was sufficient to justify a trial.10
surrounding not only the science but also the
These concerns triggered a February 2010
ethics of drug­safety research,2 many of which letter from members of Congress to the FDA de­
came to the fore in the heated public debate manding a justification for the trial and alleg­
about the Thiazolidinedione Intervention with ing that the consent form did not provide ade­
Vitamin D Evaluation (TIDE) trial, which com­ quate risk information.11 In response, FDA
pared the cardiovascular outcomes of long­term Commissioner Margaret Hamburg expanded the
treatment with rosiglitazone with those of pio­ FDA investigation of the safety of rosiglitazone,
glitazone (Actos, Takeda) in patients with type 2 obtained advice from an FDA advisory commit­
diabetes.3 At the request of the FDA, an Institute tee, and asked the IOM to convene our commit­
of Medicine (IOM) committee, on which we tee.6 Although the FDA advisory committee rec­
served, was convened to examine the ethics and ommended that the TIDE trial be continued if
science of FDA­required postmarketing safety re­ rosiglitazone was permitted to remain on the
search. In this article, we review the key ethics market, in September 2010, the FDA halted the
findings from the committee’s May 1, 2012, re­ trial and placed stringent new restrictions on
port4 and offer some reflections on the chal­ the availability of rosiglitazone.12,13
The TIDE experience made the FDA appreci­
ate the need for greater attention to the ethics
of postmarketing research. First, it posed ques­
tions about what standard of evidence about drug
In May 2008, the FDA ordered the manufacturer risk justifies a decision by the FDA to require
of rosiglitazone, GlaxoSmithKline, to conduct a postmarketing research, particularly randomized
trial in response to evidence from meta­analyses trials, as well as what evidence could render
that rosiglitazone was associated with a higher such trials unacceptable. Second, it raised ques­
risk of myocardial infarction and death from car­ tions about what ethical obligations the FDA
diovascular causes than placebo or medications has to patients who participate in these studies.
that were not based on nonthiazolidinedione Finally, it highlighted a potential FDA role in
comparators.5,6 Other studies suggested that pio­ ensuring that institutional review boards (IRBs)
glitazone, an alternative thiazolidinedione, was are completely informed in their efforts to pro­
not associated with such risks.7,8 Before enroll­ tect study participants. Although major deficien­
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T h e n e w e ng l a n d j o u r na l o f m e dic i n e
cies with the TIDE consent form were identified
The committee argued that when the FDA re­
by some FDA scientists and, later, by the IOM quires a postmarketing study, it assumes a mea­
committee (Table 1),4,9 the TIDE investigators sure of ethical responsibility for the welfare of
countered that it had been approved by “480 the study participants; exercise of that responsi­
ethics committees and IRBs.”14 However, the bility cannot be handed off to contractors or the
language of the consent form, the trial design, industry sponsor. The responsibility is particu­
and the materials supporting the justification of larly strong when the patients’ treatment is de­
the trial raised a question for the IOM commit­ termined by the study, such as in a randomized
tee about whether these bodies adequately under­ trial, linking any adverse outcomes directly to a
stood the nature of the evidence that gave rise regulatory decision to require a study of that
to the trial. The IOM committee proposed a type. This determination led to one of the most
framework for evaluating the ethics of FDA­ important recommendations from the IOM com­
required postmarketing research15 and made a mittee: the responsibilities of the FDA to research
number of ethics findings and recommendations.4 participants mean that it should mandate a ran­
domized design only if the FDA “has concluded
ETHICAL RESPONSIBILITIES OF THE FDA
that an observational study could not provide
The IOM committee began by noting that the the necessary information [to help answer the
public health mission of the FDA gives rise to important public health question at issue], that
potentially competing ethical obligations “to pro­ an RCT [randomized, controlled trial] is likely to
tect the public’s health by having strong science generate the information within the necessary
on which to base regulatory decisions” and “to timeframe, and that the necessary RCT is ethi­
protect participants in research that it requires.”4 cally acceptable.” This recommendation com­
Requiring a postmarketing study is an ethical ports with but adds some further conditions to
decision, reflecting a weighing of these values.
the current legal authority of the FDA under the
The committee described the conditions that FDA Amendments Act of 2007, which empowers
must be present to justify a decision to require a the agency to require a randomized trial if it
postmarketing study. The FDA should require cannot obtain the data it needs from an obser­
postmarketing research only when, first, the un­ vational study.1
certainty about the benefit–risk balance of a
In light of the critiques of the TIDE trial as
drug is so great that a responsible decision inherently unethical, the committee addressed
about its regulatory status cannot be made on the justifiability of trials in which participants
the basis of existing evidence; second, the re­ may encounter a net increase in risk, as com­
search will reduce this uncertainty; third, the pared with ordinary clinical care, but no realis­
FDA will use the research results expeditiously tic prospect of personal benefit. It argued that
to make a regulatory decision; and fourth, suffi­ such trials can be justified only if they are nec­
cient protections for research participants can be essary to answer a critically important public
health question, if the potential risk is accept­
Table 1. Major Deficiencies in the Informed-Consent Form for the TIDE Trial.*Consent ElementSpecific Deficiencies
Did not clearly explain that the purpose of the study was to definitively establish that rosiglitazone in-
volved a significantly higher risk of serious harms than pioglitazone
Title included minor intervention (vitamin D) whose effects were not a subject of FDA concern
Did not convey that the FDA was concerned primarily about the safety of rosiglitazone and was requiring
the sponsor to conduct the TIDE trial to investigate safety signals
Submerged cardiovascular risks associated with rosiglitazone in a list of outcomes related to potential effects
of vitamin D on cancer and bone fractures
Characterized previous studies as having provided conflicting findings concerning the cardiovascular
safety of rosiglitazone, when the weight of the evidence was against rosiglitazone
Inadequate explanation of alterna- Did not disclose that the current clinical standard of care had moved away from the use of rosiglitazone
Did not mention that the American Diabetes Association had recommended that rosiglitazone not be used
* Adapted from the Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs, Institute of Medicine,4 and Graham
and Gelperin.9 FDA denotes Food and Drug Administration, and TIDE Thiazolidinedione Intervention with Vitamin D Evaluation.
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able and minimized, and if special safeguards
are in place, including a highly explicit informed­ sures to strengthen the consent process in order
consent process to ensure that patients under­ to maximize patients’ understanding of the con­
stand that they are potentially shouldering addi­ text in which the trial is being conducted, includ­
tional risk solely to contribute to the public good. ing what is already known about the risks asso­
Specific actions that the FDA should take to ciated with the drug. The report discussed both
meet its ethical obligations include specifying the specific disclosures in the informed­consent
study design, title, end points, and primary analy­ form and special efforts that could be made to
ses; identifying design features that it views as ensure adequate comprehension of complex in­
ethically and scientifically indispensable; and, formation regarding risks (Table 2). To assist
for clinical trials, specifying a safety­monitoring IRBs, the committee recommended that the FDA
scheme. The committee recommended that the issue guidance interpreting current informed­
FDA routinely communicate with IRBs about re­ consent regulatory requirements in the context
quired postmarketing studies — for example, by of required postmarketing studies.
issuing a letter to accompany IRB applications
that conveys information that is material to the
IRB’s determination of the ethics of the research,
as well as providing additional communications
over the life of the study as warranted by new Because a true picture of the benefit–risk profile
information about the drug or by changes in pro­ of a drug only emerges over time, two different
fessional practice. The committee also believed IOM committees have stressed the need for the
that the FDA was ethically obligated to actually FDA to fully embrace a “life­cycle approach” to
use the findings from required studies to make drug regulation, in which its obligations to pro­
tect public health are taken as seriously once a
drug is on the market as they are before approval
INFORMED-CONSENT PROCESS FOR REQUIRED
is granted.4,16 Postmarketing regulatory oversight
POSTMARKETING TRIALS
is assuming heightened importance as the FDA
The IOM committee emphasized that the ade­ accrues additional authority to fast­track drugs
quacy of the informed­consent process is only for approval on the basis of more limited evi­
one element in the ethics of FDA­required post­ dence than was previously required in order to
marketing research. Other central, and indeed address unmet medical needs and accelerate in­
prior, features include ensuring that the selec­ novation.17-19 This changing landscape raises
tion of participants is equitable and that the level several challenges for ensuring the ethical con­
of risk to which they are exposed is acceptable. duct of research with approved drugs and balanc­
The committee also recognized, however, that ing societal interests in drug innovation and drug
there are challenges to achieving meaningful in­ safety. We highlight two of these challenges here.
formed consent in postmarketing trials of drugs
First, not all postmarketing research is ethi­
for which there is a signal indicating the possi­ cally equivalent. The TIDE trial represented an
bility of drug­related harm. In such cases, there iconic kind of postmarketing study: an FDA­
is a suspicion that the benefits of the drug may required randomized trial to study a drug whose
not justify its risks and often that it may have a benefit–risk profile was under a cloud of suspi­
worse benefit–risk profile than alternative drugs cion and at a time when alternative treatments
available to treat the same condition. The com­ were available, albeit not all well studied. The
mittee concluded that for postmarketing trials risks to patients of participating in the trial
of such drugs, there are “heightened obligations probably outweighed the prospect of direct ben­
to ensure that potential research participants un­ efit. By contrast, when the FDA requires an ob­
derstand the risks posed by study enrollment.” 4 servational study that uses previously collected
This was of particular importance for rosiglita­ data, the clinical experience of the participants
zone, because the cardiovascular problem it ap­ is unaffected, the risks incurred are not at the
peared to cause was the same outcome that behest of the FDA, and ethical concerns are
good diabetic control was supposed to improve largely confined to confidentiality and the right
— in other words, if this elevation in risk were to control one’s medical information.
real, there could be little offsetting benefit.
Both of these scenarios can be distinguished
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T h e n e w e ng l a n d j o u r na l o f m e dic i n e
Table 2. Mechanisms for Strengthening the Informed-Consent Process for Postmarketing Drug-Safety Studies.*Consent ElementInformation to Be Conveyed
Clear explanation of why a new study is required even though the FDA already found the
drug to have an acceptable benefit–risk profile
Meaningful, balanced summary of existing evidence about the safety of the study drug
Explanation of why experts deem it reasonable to ask patients to participate in the study,
If applicable, a statement that participants are being asked to assume a higher risk than
they would be likely to encounter under the current clinical standard of care solely for
the purpose of answering an important public health question
Drug-risk information should go beyond a bul et-point list of possible side effects, indicating
where the weight of evidence falls concerning the likelihood that serious harms will oc-
cur and the extent of current scientific uncertainty
At a minimum, disclosures should include boxed warnings, a “major statement” in direct-
to-consumer advertisements, salient findings from FDA advisory committees, and a
summary of findings from peer-reviewed studies
Clear explanation of how the care that patients receive in the study may differ from the
care they currently receive or would be likely to receive if they did not enroll
If applicable, a statement that the current clinical standard of care has moved away from
use of the study drug, and an explanation of why
Ongoing communication of Timely, comprehensible communications if safety signals intensify over the course of the study
relevant new information Recommendation that study participants consult with their treating physician to determine
whether continued study participation is prudent in light of new information
* Adapted from the Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs, Institute of
from the context in which a phase 4 trial is re­ ethical difference between FDA­required post­
quired as a condition of an accelerated drug ap­ marketing research and comparative­effective­
proval and is initiated soon thereafter. Here, the ness research initiated by academic investiga­
trial requirement is not imposed because of a tors. By contrast, a comparative­effectiveness
newly emerging concern about a drug already in study of two widely used drugs that is not oc­
clinical use but because additional evidence is casioned by heightened concern about the risks
needed to confirm the initial judgment that the of one drug relative to the other is markedly dif­
benefits of a new drug are likely to outweigh its ferent, ethically, from a study required by the
risks. Often, this initial judgment is based on FDA to pursue a safety signal that is already of
the use of a surrogate end point for drug bene­ such concern that practice patterns are shifting,
fit, not on the clinical outcomes that matter even if both studies use randomized designs.
most. Especially when the new drug targets an
These differences highlight the need for IRBs
unmet medical need, it may be in the patients’ to be sensitive to the place where a study falls
best interest to take it, pending further timely within the life cycle of a drug and to the reason
research. The ensuing trial is undertaken to for the research. Depending on who is initiating
confirm the improvement in clinical outcomes the research, for what reasons, and when, the
predicted by the surrogate — a different epis­ same study design may have very different rami­
temic and ethical situation than that in which fications for the benefit–risk balance of the
substantial evidence suggests that the surrogate study and what patients need to know in order
is misleading or that other harms might offset a to provide meaningful informed consent. Trials
that may be regarded as unethical late in the
The volume of phase 4 and other research life cycle because of accumulated evidence can
with FDA­approved drugs is increasing, not only be much easier to initiate earlier if the need for
because of the expanded authority of the FDA to additional research is anticipated and planned
require such research but also because of the at the time of initial approval. In the case of
growing volume of comparative­effectiveness re­ rosiglitazone, this need could have been antici­
search. In some cases, there may be no or little pated from preapproval data showing an adverse
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effect on serum lipids as well as the use of a late a persuasive reason why it would result in
surrogate end point (glycemic control) for a competitive harm and the FDA determines that
this harm outweighs the public health benefits
Second, the experience with rosiglitazone of releasing the information.
underscored the fragility of our current system
of discovering risks associated with drugs. This
system relies heavily on drug sponsors and FDA
scientists to conduct safety analyses on the ba­ The experience with rosiglitazone and the TIDE
sis of data from clinical trials, some or all of trial offers a lesson in how our current approach
which are not publicly available, and to release to the oversight of drug­safety and postmarket­
findings to the public. It has been shown repeat­ ing research can fail both the public and the re­
edly that the published record can misrepresent search participants. Although terminating the
evidence known to the FDA.21,22 In the case of TIDE trial was justifiable, it left regulators with
rosiglitazone, scientists from GlaxoSmithKline highly suggestive but nondefinitive data on the
and the FDA had information from 42 clinical relative safety of rosiglitazone and the closest
trials, of which only 7 were published and the clinical alternative, pioglitazone.32
others were inaccessible. Triggered by concerns
Reactive policymaking is tempting but prob­
expressed by the World Health Organization in lematic. The history of regulation of human sub­
2006, GlaxoSmithKline conducted and shared jects research suggests that rules that are “born
with the FDA a meta­analysis of the safety of in scandal and reared in protectionism”33 often
rosiglitazone that used these data, confirming a fall short of providing meaningful protections
possibly elevated risk of ischemic events, but to research participants and that, once adopted,
neither these results nor the primary trial results regulations can ossify and become difficult to
were shared with the public until an unrelated dislodge. Nevertheless, the IOM committee’s re­
court settlement forced GlaxoSmithKline to re­ port makes a number of actionable recommen­
lease its complete clinical­trial data.23 This ac­ dations that the FDA can implement under its
cess led to the published meta­analysis by inde­ existing authority.34 In addition, appointment of
pendent researchers that made these data and an independent ethics advisory board would
strengthen the decision making of the FDA as it
It is often the work of independent scientists confronts emerging ethical challenges — both
that has highlighted critical safety problems with those arising from required postmarketing tri­
approved drugs.5,24-29 Yet currently, data from pre­ als and those stemming from powerful new
marketing studies that are submitted as part of drug surveillance systems, such as the FDA’s
a new drug application or a supplemental new Sentinel Initiative. As the pace of the translation
drug application are largely shielded from release of discoveries from bench to bedside continues
to external scientists and the public owing to to intensify, so too does the imperative for
concerns about a competitive disadvantage to thoughtful ethical governance throughout the
drug sponsors.30,31 The IOM committee stopped life cycle of a drug.
short of calling on the FDA to increase public
The views expressed in this article are those of the authors
access to such data but recommended that the and, except where noted, do not represent the official position of
the Institute of Medicine or of the committee that produced the
agency initiate a process to determine ways to report discussed in this article.
“appropriately balance public health, privacy, and
Drs. Faden and Goodman chaired, and Dr. Mello was a mem­
proprietary interests to facilitate disclosure” of ber of, the Institute of Medicine committee that produced the
relevant data.4 Greater transparency would better
Disclosure forms provided by the authors are available with
equip independent scientists to investigate early the full text of this article at NEJM.org.
safety signals.31 Consideration should be given
We thank the other IOM committee members for contribut­
to making drug­safety data from clinical trials From the Department of Health Policy and Management, Har-
available to the public on request once the FDA vard School of Public Health, Boston (M.M.M.); the Depart-
has reached a decision regarding a new drug ap­ ments of Medicine and Health Research and Policy, Stanford
plication or a supplemental new drug application University School of Medicine, Stanford, CA (S.N.G.); and the
Berman Institute of Bioethics, Johns Hopkins University, Balti-
or once the manufacturer has abandoned the more (R.R.F.).
application, unless the manufacturer can articu­ This article was published on August 22, 2012, at NEJM.org.
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